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The escalating prevalence of Parkinson's disease (PD) underscores the need for innovative therapeutic interventions since current palliative measures, including the standard l-Dopa formulations, face challenges of tolerance and side effects while failing to address the underlying neurodegenerative processes. Here, we introduce DAD9 , a novel conjugate molecule that aims to combine symptomatic relief with disease-modifying strategies for PD. Crafted through knowledge-guided chemistry, the molecule combines a nonantibiotic doxycycline derivative with dopamine, preserving neuroprotective attributes while maintaining dopaminergic agonism. This compound exhibited no off-target effects on PD-relevant cell functions and sustained antioxidant and anti-inflammatory properties of the tetracycline precursor. Furthermore, it effectively interfered with the formation and seeding of toxic α-synuclein aggregates without producing detrimental oxidative species. In addition, DAD9 was able to activate dopamine receptors, and docking simulations shed light onto the molecular details of this interaction. These findings position DAD9 as a potential neuroprotective dopaminergic agonist, promising advancements in PD therapeutics.

Partial agonist activity at the dopamine D 2 receptor (D 2 R) is the primary pharmacological feature of the third-generation antipsychotics─aripiprazole, brexpiprazole, and cariprazine. However, all these drugs share a common phenyl-piperazine moiety as the primary pharmacophore. In this study, we designed and synthesized a series of novel compounds based on the 2-phenylcyclopropylmethylamine (PCPMA) scaffold and studied their pharmacological activity at the D 2 R. A number of potent D 2 R partial agonists were identified through binding affinity screening and functional activity profiling in both G protein and β-arrestin assays. The structure-functional activity relationship results showed that the spacer group is crucial for fine-tuning the intrinsic activity of these compounds. Compounds (+)- 14j and (+)- 14l showed good pharmacokinetic properties and an unexpected selectivity against the serotonin 2A (5-HT 2A ) receptor. Preliminary suppressive effects in a mouse hyperlocomotion model proved that these PCPMA-derived D 2 R partial agonists are effective as potential novel antipsychotics.

The dopamine D2/D3 receptor (D 2 R/D 3 R) agonists are used as therapeutics for Parkinson's disease (PD) and other motor disorders. Selective targeting of D 3 R over D 2 R is attractive because of D 3 R's restricted tissue distribution with potentially fewer side-effects and its putative neuroprotective effect. However, the high sequence homology between the D 2 R and D 3 R poses a challenge in the development of D 3 R selective agonists. To address the ligand selectivity, bitopic ligands were designed and synthesized previously based on a potent D 3 R-preferential agonist PF592,379 as the primary pharmacophore (PP). This PP was attached to various secondary pharmacophores (SPs) using chemically different linkers. Here, we characterize some of these novel bitopic ligands at both D 3 R and D 2 R using BRET-based functional assays. The bitopic ligands showed varying differences in potencies and efficacies. In addition, the chirality of the PP was key to conferring improved D 3 R potency, selectivity, and G protein signaling bias. In particular, compound AB04-88 exhibited significant D 3 R over D 2 R selectivity, and G protein bias at D 3 R. This bias was consistently observed at various time-points ranging from 8 to 46 min. Together, the structure-activity relationships derived from these functional studies reveal unique pharmacology at D 3 R and support further evaluation of functionally biased D 3 R agonists for their therapeutic potential.

Even today, the role of the histamine H 2 receptor (H 2 R) in the central nervous system (CNS) is widely unknown. In previous research, many dimeric, high-affinity and subtype-selective carbamoylguanidine-type ligands such as UR-NK22 (5, pK i  = 8.07) were reported as H 2 R agonists. However, their applicability to the study of the H 2 R in the CNS is compromised by their molecular and pharmacokinetic properties, such as high molecular weight and, consequently, a limited bioavailability. To address the need for more drug-like H 2 R agonists with high affinity, we synthesized a series of monomeric (thio)carbamoylguanidine-type ligands containing various spacers and side-chain moieties. This structural simplification resulted in potent (partial) agonists (guinea pig right atrium, [ 35 S]GTPγS and β-arrestin2 recruitment assays) with human (h) H 2 R affinities in the one-digit nanomolar range (pK i (139, UR-KAT523): 8.35; pK i (157, UR-MB-69): 8.69). Most of the compounds presented here exhibited an excellent selectivity profile towards the hH 2 R, e.g. 157 being at least 3800-fold selective within the histamine receptor family. The structural similarities of our monomeric ligands to pramipexole (6), a dopamine receptor agonist, suggested an investigation of the binding behavior at those receptors. The target compounds were (partial) agonists with moderate affinity at the hD 2long R and agonists with high affinity at the hD 3 R (e.g. pK i (139, UR-KAT523): 7.80; pK i (157, UR-MB-69): 8.06). In summary, we developed a series of novel, more drug-like H 2 R and D 3 R agonists for the application in recombinant systems in which either the H 2 R or the D 3 R is solely expressed. Furthermore, our ligands are promising lead compounds in the development of selective H 2 R agonists for future in vivo studies or experiments utilizing primary tissue to unravel the role and function of the H 2 R in the CNS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Dopamine D 2 receptors (D 2 Rs) are major targets in the treatment of psychiatric and neurodegenerative diseases. As with many other G protein-coupled receptors (GPCRs), D 2 Rs interact within the cellular membrane, leading to a transient receptor homo- or heterodimerization. These interactions are known to alter ligand binding, signaling, and receptor trafficking. Bivalent ligands are ideally suited to target GPCR dimers and are composed of two pharmacophores connected by a spacer element. If properly designed, bivalent ligands are able to engange the two orthosteric binding sites of a GPCR dimer simultaneously. Taking advantage of previously developed ligands for heterodimers of D 2 R and the neurotensin receptor 1 (NTSR1), we synthesized homobivalent ligands targeting D 2 R. Employing bioluminescence resonance energy transfer, we found that the bivalent ligands 3b and 4b comprising a 92-atom spacer are able to foster D 2 R-homodimerization while simultaneously reducing interactions of D 2 R with NTSR1. Both receptors are coexpressed in the central nervous system and involved in important physiological processes. The newly developed bivalent ligands are excellent tools to further understand the pharmacological consequences of D 2 R homo- and heterodimerization. Not limited to the dopaminergic system, modifying class A GPCRs' dynamic equilibrium between monomers, homomers, and heteromers with bivalent ligands may represent a novel pharmacological concept paving the way toward innovative drugs.

Employing two different alkyne-modified dopamine agonists to construct bivalent compounds via click chemistry resulted in the identification of a bivalent ligand (11c) for dopamine D 2 receptor homodimer, which, compared to its parent monomeric alkyne, showed a 16-fold higher binding affinity for the dopamine D 2 receptor and a 5-fold higher potency in a cAMP assay in HEK 293T cells stably expressing D 2 R. Molecular modeling revealed that 11c can indeed bridge the orthosteric binding sites of a D 2 R homodimer in a relaxed conformation via the TM5-TM6 interface and allows to largely rationalize the results of the receptor assays., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

MLS1082 is a structurally novel pyrimidone-based D1-like dopamine receptor positive allosteric modulator. Potentiation of D1 dopamine receptor (D1R) signaling is a therapeutic strategy for treating neurocognitive disorders. Here, we investigate the relationship between D1R potentiation and two prominent structural features of MLS1082, namely the pendant N-aryl and C-alkyl groups on the pyrimidone ring. To this end, we synthesized 24 new analogues and characterized their ability to potentiate dopamine signaling at the D1R and the closely related D5R. We identified structure-activity relationship trends for both aryl and alkyl modifications and our efforts afforded several analogues with improvements in activity. The most effective analogues demonstrated an approximately 8-fold amplification of dopamine-mediated D1R signaling. These findings advance the understanding of structural moieties underlying the activity of pyrimidone-based D1R positive allosteric modulators., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

2-Phenylcyclopropylmethylamine (PCPMA) analogues have been reported as selective serotonin 2C agonists. On the basis of the same scaffold, we designed and synthesized a series of bitopic derivatives as dopamine D3R ligands. A number of these new compounds show a high binding affinity for D3R with excellent selectivity. Compound (1 R ,2 R )- 22e and its enantiomer (1 S ,2 S )- 22e show a comparable binding affinity for the D3R, but the former is a potent D3R agonist, while the latter acts as an antagonist. Molecular docking studies revealed different binding poses of the PCPMA moiety within the orthosteric binding pocket of the D3R, which might explain the different functional profiles of the enantiomers. Compound (1 R ,2 R )- 30q shows a high binding affinity for the D3R ( K i = 2.2 nM) along with good selectivity, as well as good bioavailability and brain penetration properties in mice. These results reveal that the PCPMA scaffold may serve as a privileged scaffold for the design of aminergic GPCR ligands.

Because of the large degree of homology among dopamine D 2 -like receptors, discovering ligands capable of discriminating between the D 2 , D 3 , and D 4 receptor subtypes remains a significant challenge. Previous work has exemplified the use of bitopic ligands as a powerful strategy in achieving subtype selectivity for agonists and antagonists alike. Inspired by the potential for chemical modification of the D 3 preferential agonists (+)-PD128,907 ( 1 ) and PF592,379 ( 2 ), we synthesized bitopic structures to further improve their D 3 R selectivity. We found that the (2 S ,5 S ) conformation of scaffold 2 resulted in a privileged architecture with increased affinity and selectivity for the D 3 R. In addition, a cyclopropyl moiety incorporated into the linker and full resolution of the chiral centers resulted in lead compound 53 and eutomer 53a that demonstrate significantly higher D 3 R binding selectivities than the reference compounds. Moreover, the favorable metabolic stability in rat liver microsomes supports future studies in in vivo models of dopamine system dysregulation.

Functionally selective G protein-coupled receptor ligands are valuable tools for deciphering the roles of downstream signaling pathways that potentially contribute to therapeutic effects versus side effects. Recently, we discovered both G i/o -biased and β-arrestin2-biased D 2 receptor agonists based on the Food and Drug Administration (FDA)-approved drug aripiprazole. In this work, based on another FDA-approved drug, cariprazine, we conducted a structure-functional selectivity relationship study and discovered compound 38 (MS1768) as a potent partial agonist that selectively activates the G i/o pathway over β-arrestin2. Unlike the dual D 2 R/D 3 R partial agonist cariprazine, compound 38 showed selective agonist activity for D 2 R over D 3 R. In fact, compound 38 exhibited potent antagonism of dopamine-stimulated β-arrestin2 recruitment. In our docking studies, compound 38 directly interacts with S193 5.42 on TM5 but has no interactions with extracellular loop 2, which appears to be in contrast to the binding poses of D 2 R β-arrestin2-biased ligands. In in vivo studies, compound 38 showed high D 2 R receptor occupancy in mice and effectively inhibited phencyclidine-induced hyperlocomotion.

We have developed a series of carbazole-derived compounds based on our hybrid D 2 /D 3 agonist template to design multifunctional compounds for the symptomatic and disease-modifying treatment of Parkinson's disease (PD). The lead molecules (-)-11b (D-636), (-)-15a (D-653), and (-)-15c (D-656) exhibited high affinity for both D 2 and D 3 receptors and in GTPγS functional assay, the compounds showed potent agonist activity at both D 2 and D 3 receptors (EC 50 (GTPγS); D 2 = 48.7 nM, D 3 = 0.96 nM for 11b, D 2 = 0.87 nM, D 3 = 0.23 nM for 15a and D 2 = 2.29 nM, D 3 = 0.22 nM for 15c). In an animal model of PD, the test compounds exhibited potent in vivo activity in reversing hypolocomotion in reserpinized rats with a long duration of action compared to the reference drug ropinirole. In a cellular antioxidant assay, compounds (-)-11b, (-)-15a, and (-)-15c exhibited potent activity in reducing oxidative stress induced by neurotoxin 6-hydroxydopamine (6-OHDA). Also, in a cell-based PD neuroprotection model, these lead compounds significantly increased cell survival from toxicity of 6-OHDA, thereby producing a neuroprotective effect. Additionally, compounds (-)-11b and (-)-15a inhibited aggregation and reduced toxicity of recombinant alpha synuclein protein in a cell based in vitro assay. These observations suggest that the lead carbazole-based dopamine agonists may be promising multifunctional molecules for a viable symptomatic and disease-modifying therapy of PD and should be further investigated.

The dopamine D1 receptor (D1R) is essential for neurotransmission in various brain pathways where it modulates key functions including voluntary movement, memory, attention and reward. Not surprisingly, the D1R has been validated as a promising drug target for over 40 years and selective activation of this receptor may provide novel neurotherapeutics for neurodegenerative and neuropsychiatric disorders. Several pharmacokinetic challenges with previously identified small molecule D1R agonists have been recently overcome with the discovery and advancement of new ligands, including drug-like non-catechol D1R agonists and positive allosteric modulators. From this, several novel molecules and mechanisms have recently entered clinical studies. Here we review the major classes of D1R selective ligands including antagonists, orthosteric agonists, non-catechol biased agonists and positive allosteric modulators, highlighting their structure-activity relationships and medicinal chemistry. Recent chemistry breakthroughs and innovative approaches to selectively target and activate the D1R also hold promise for creating pharmacotherapy for several neurological diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The total synthesis of (±)-quinagolide, which is a D 2 receptor agonist, was accomplished via a ceric ammonium nitrate (CAN)-mediated regioselective azidoalkoxylation of enol ether route. Key features of the synthesis include Claisen rearrangement, PPTS (pyridinium p-toluenesulfonate)-catalyzed one-pot acetal deprotection, followed by a diastereoselective Henry reaction, which enables construction of the required trans ring junction and CAN-mediated regioselective azidoalkoxylation of enol ether. The PPTS-catalyzed intramolecular diastereoselective Henry reaction to fix three contiguous stereocenters on tetrahydronaphthalene and the first-of-its-kind synthesis of the 3-azidopiperidine skeleton, using a CAN-mediated regioselective azidoalkoxylation of enol ether, are important findings of the present work.

β-Arrestin biased G protein-coupled receptor ligands represent important molecular probes and may increase favorable drug action and safety as novel therapeutics. Starting from recently discovered hydroxy-substituted heterocyclic piperazine scaffolds, we have developed a series of dopamine D 2 receptor ligands with a pyrazolo[1,5-a]pyridine as secondary pharmacophore that is functionalized in position 3 by a formyl or hydroxyiminomethyl substituent. The ligands, especially the benzoxazinone 9d, were found to stimulate substantial β-arrestin-2 recruitment, while being nearly devoid of activity in a GTPγS binding assay. Investigating a new series of truncated analogs lacking a secondary pharmacophore, considerable β-arrestin-2 recruitment in the absence of G protein activation was found, when a 5-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one was combined with an N-propyl-substituted 1,4-diazepane (15c). Although 15c displayed reduced potency compared to 9d, the dose-response curves indicate that a hydroxy-substituted heterocyclic primary pharmacophore is sufficient for the functionally selective activation of D 2 R., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Parkinson's disease (PD) is a progressive neurodegenerative disorder, and development of disease-modifying treatment is still an unmet medical need. Considering the implication of free iron(II) in PD, we report here the design and characterization of a novel hybrid iron chelator, (-)-12 (D-607) as a multitarget-directed ligand against PD. Binding and functional assays at dopamine D 2 /D 3 receptors indicate potent agonist activity of (-)-12. The molecule displayed an efficient preferential iron(II) chelation properties along with potent in vivo activity in a reserpinized PD animal model. The compound also rescued PC12 cells from toxicity induced by iron delivered intracellularly in a dose-dependent manner. However, Fe 3+ selective dopamine agonist 1 and a well-known antiparkinsonian drug pramipexole produced little to no neuroprotection effect under the same experimental condition. These observations strongly suggest that (-)-12 should be a promising multifunctional lead molecule for a viable symptomatic and disease modifying therapy of PD.

Our ongoing drug development endeavor to design compounds for symptomatic and neuroprotective treatment of Parkinson's disease (PD) led us to carry out a structure activity relationship study based on dopamine agonists pramipexole and 5-OHDPAT. Our goal was to incorporate structural elements in these agonists in a way to preserve their agonist activity while producing inhibitory activity against aggregation of α-synuclein protein. In our design we appended various catechol and related phenol derivatives to the parent agonists via different linker lengths. Structural optimization led to development of several potent agonists among which (-)-8a, (-)-14 and (-)-20 exhibited potent neuroprotective properties in a cellular PD model involving neurotoxin 6-OHDA. The lead compounds (-)-8a and (-)-14 were able to modulate aggregation of α-synuclein protein efficiently. Finally, in an in vivo PD animal model, compound (-)-8a exhibited efficacious anti-parkinsonian effect., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The use of dopaminergic agonists is key in the treatment of Parkinson's disease and related central nervous system (CNS) neurodegenerative disorders. Despite there are a number of commercialized dopaminergic agonists that are currently being used successfully in the first stages of the disease, they often fail to provide sustained clinical benefit for a long period due to the appearance of side-effects such as augmentation, sleepiness, nausea, hypothension, and compulsive behaviors among others. New dopaminergic agonists with less side effects are being developed. These novel compounds offer an alternative when the disease progresses and patients fail to respond to standard dopaminergic treatments or side-effects increased. Chemistry, and in particular chemical synthesis, has played a major role in bringing synthetic dopaminergic agonists to the clinic and continues to be crucial for the development of new and necessary drugs for long-term treatments with less undesired side effects. A number of structural modifications of parent compounds have led to enhanced agonism but also partial agonism or even antagonism of one or more dopamine receptors. In some cases, these activities are accompanied by agonist effect at serotonin receptors which suggests a potential clinical application in the treatment of schizophrenia In this review, chemical synthesis of dopaminergic agents, their affinity, and the corresponding agonist/antagonist effects will be highlighted.

We designed, prepared and tested a set of structural analogs 1-4 as new hybrid compounds by incorporating, through a common alkyl chain of variable length, the pharmacophoric elements of N-n-alkyl nicotinium salts (non-α7 nicotinic acetylcholine receptors antagonists) and of 7-hydroxy-2-(aminomethyl)chromanes (dopaminergic D2 receptor agonists). The target compounds, which were assayed in binding experiments and electrophysiological, functional and Erk1/2 activation tests, essentially combined the pharmacological profiles of their individual receptor ligands. Among the studied derivatives, hybrid 2, one of the shortest homologs, in addition to the antagonist nicotinic profile similar to the other three congeners, behaved as a high affinity ligand at the investigated heteromeric nAChRs and as a low efficacy agonist at D2Rs. These bifunctional derivatives represent novel pharmacological tools in the study of nicotine addiction., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

In recent decades, many compounds with central dopaminergic activity have been designed, synthesized and evaluated pharmacologically. However, it has not been possible to obtain a drug able to improve or cure diseases involving dopaminergic regulation in the central nervous system, such as Parkinson's disease and schizophrenia, among others. Taking into consideration the term "atypical pharmacophore" and from the compound 5, the aralkyl fragment was incorporated, and the compounds 10, 11, 13a-h and 14a-h were synthesized. Both the compounds 10 and 13a-h under its methoxylated form and the compounds 11 and 14a-h under the phenolic form, were evaluated to determine their pharmacologically agonistic and antagonistic effects on central dopaminergic activity. For this, the effect of intracerebroventricular injection of said compounds on the hydromineral balance and stereotyped behavior in rats, was determined. The results of the preliminary pharmacological evaluation show a centrally acting action through dopamine mechanisms, in which the compounds 10, 11, 13d-h and 14a showed responses as agonists, whereas compounds 14b-h, had responses as antagonists.

A series of 2-methoxyphenyl piperazine analogues containing a triazole ring were synthesized and their in vitro binding affinities at human dopamine D2 and D3 receptors were evaluated. Compounds 5b, 5c, 5d, and 4g, demonstrate high affinity for dopamine D3 receptors and moderate selectivity for the dopamine D3 versus D2 receptor subtypes. To further examine their potential as therapeutic agents, their intrinsic efficacy at both D2 and D3 receptors was determined using a forskolin-dependent adenylyl cyclase inhibition assay. Affinity at dopamine D4 and serotonin 5-HT1A receptors was also determined. In addition, information from previous molecular modeling studies of the binding of a panel of 163 structurally-related benzamide analogues at dopamine D2 and D3 receptors was applied to this series of compounds. The results of the modeling studies were consistent with our previous experimental data. More importantly, the modeling study results explained why the replacement of the amide linkage with the hetero-aromatic ring leads to a reduction in the affinity of these compounds at D3 receptors., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A relatively new strategy in drug discovery is the development of dual acting ligands. These molecules are potentially able to interact at two orthosteric binding sites of a heterodimer simultaneously, possibly resulting in enhanced subtype selectivity, higher affinity, enhanced or modified physiological response, and reduced reliance on multiple drug administration regimens. In this study, we have successfully synthesized a series of classical heterobivalent ligands as well as a series of more integrated and "drug-like" dual acting molecules, incorporating ropinirole as a dopamine D2 receptor agonist and ZM 241385 as an adenosine A2A receptor antagonist. The best compounds of our series maintained the potency of the original pharmacophores at both receptors (adenosine A2A and dopamine D2). In addition, the integrated dual acting ligands also showed promising results in preliminary blood-brain barrier permeability tests, whereas the classical heterobivalent ligands are potentially more suited as pharmacological tools.

Unlabelled: Dopamine D(2/3) receptor (D(2/3)R) agonist PET tracers are better suited for the imaging of synaptic dopaminergic neurotransmission than D(2/3)R antagonists and may also offer the opportunity to study in vivo the high-affinity state of D(2/3)R (D(2/3)RHigh). With the aim to develop (18)F-labeled D2/3R agonists suitable for widespread clinical application, we report here on the synthesis and in vitro and in vivo evaluation of a D(2/3)R agonist ligand from the aminomethyl chromane (AMC) class-(R)-2-[(4-(18)F-fluorobenzylamino)methyl]chroman-7-ol ((18)F- AMC20: )., Methods: In vitro affinities of AMC20: toward dopaminergic receptor subtypes were measured in membrane homogenates prepared from HEK293 cells expressing human dopamine receptors. Agonism of AMC20: was assessed in the arrestin recruitment assay in Chinese hamster ovary-K(1) cells expressing the long isoform of D(2)R (D(2)RLong). D(2/3)R-specific binding of (18)F- AMC20: was evaluated in brain slices of Sprague-Dawley rats by in vitro autoradiography and in living rats by in vivo small-animal PET imaging and ex vivo autoradiography. PET data were analyzed with 1- and 2-tissue compartmental models, the simplified reference tissue model, and Logan graphical analysis. Specificity of binding was tested by blocking D(2/3)R with raclopride (coincubation with 10 μM in vitro, administration of 1.0 mg/kg in vivo)., Results: In membrane homogenates, AMC20: demonstrated picomolar affinity at D(2)RHigh (mean inhibition constant [K(i)] = 85 pM) and excellent selectivity against the low-affinity state of D(2)R (D(2)RLow) (mean K(i) = 84 nM, 988-fold selectivity) and D(1)-like receptors (mean K(i) = 5,062 nM at D1R). The efficacy of AMC20: was 90% of that of dopamine in the arrestin recruitment assay. Up to 70% of total binding of (18)F- AMC20: in the D2/3R-rich striatum in rat brain slices was D(2/3)R-specific; in living rats, the uptake ratio between the striatum and the D(2/3)R-poor cerebellum reached 2.0-2.5, depending on the measurement method. Radiometabolites of (18)F- AMC20: did not enter the brain. Striatal binding potential of (18)F- AMC20: varied between 0.49 and 0.59 depending on the estimation method. Pretreatment with 1 mg of raclopride per kilogram reduced the apparent specific binding of (18)F- AMC20: in the striatum., Conclusion: (18)F- AMC20: shows specific binding to D(2/3)R in the striatum of living rats. Further optimization of the chemical structure of (18)F- AMC20: can lead to (18)F-labeled D(2/3) agonist PET tracers more suitable for in vivo clinical application., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

A novel scaffold derived from l-SPD with a substituted thiophene group in the D ring were designed, synthesized, and evaluated for their binding affinities at dopamine (D1, D2 and D3) and serotonin (5-HT1A and 5-HT2A) receptors. Most of the tetracyclic compounds exhibited higher affinities for D2 and 5-HT1A receptors than l-SPD, while compound 23 e showed the highest Ki value of 7.54 nM at D2 receptor which was 14 times more potent than l-SPD. Additionally, compounds 23 d and 23 e were more potent than l-SPD at D3 receptor. According to the functional assays, 23 d and 23 e were demonstrated as full antagonists at D1 and D2 receptors and full agonists at 5-HT1A receptor. Since the combination of D2 antagonism and 5-HT1A agonism is considered effective in treating both the positive and negative symptoms of schizophrenia, these novel compounds are implicated as potential therapeutic agents., (Copyright © 2014. Published by Elsevier Ltd.)

We have developed a series of dihydroxy compounds and related analogues based on our hybrid D2/D3 agonist molecular template to develop multifunctional drugs for symptomatic and neuroprotective treatment for Parkinson's disease (PD). The lead compound (-)-24b (D-520) exhibited high agonist potency at D2/D3 receptors and produced efficacious activity in the animal models for PD. The data from thioflavin T (ThT) assay and from transmission electron microscopy (TEM) analysis demonstrate that D-520 is able to modulate aggregation of alpha-synuclein (αSN). Additionally, coincubation of D-520 with αSN is able to reduce toxicity of preformed aggregates of αSN compared to control αSN alone. Finally, in a neuroprotection study with dopaminergic MN9D cells, D-520 clearly demonstrated the effect of neuroprotection from toxicity of 6-hydroxydopamine. Thus, compound D-520 possesses properties characteristic of multifunctionality conducive to symptomatic and neuroprotective treatment of PD.

Imaging of dopamine D2/3 receptors (D2/3R) can shed light on the nature of several neuropsychiatric disorders in which dysregulation of D2/3R signaling is involved. Agonist D2/3 tracers for PET/SPECT imaging are considered to be superior to antagonists because they are more sensitive to dopamine concentrations and may selectively label the high-affinity receptor state. Carbon-11-labeled D2/3R agonists have been developed, but these short-lived tracers can be used only in centers with a cyclotron. Here, we report the development of a series of novel D2R agonist compounds based on the 2-aminomethylchromane (AMC) scaffold that provides ample opportunities for the introduction of longer-lived [(18)F] or [(123)I]. Binding experiments showed that several AMC compounds have a high affinity and selectivity for D2/3R and act as agonists. Two fluorine-containing compounds were [(18)F]-labeled, and both displayed specific binding to striatal D2/3R in rat brain slices in vitro. These findings encourage further in vivo evaluations.

The synthesis of a novel series of dopamine receptor agonists are described as well as their in vitro potency and efficacy on dopamine D₁ and D₂ receptors. This series was designed from pergolide and (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinolin-6-ol (PHBQ) and resulted in the synthesis of (2R,4aR,10aR)-2-methylsulfanylmethyl-4-propyl-3,4,4a,5,10,10a-hexahydro-2H-naphtho[2,3-b][1,4]oxazin-9-ol (compound 27), which has a D₁ and D₂ receptor profile similar to that of the most recently approved drug for Parkinson's disease, rotigotine., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A novel set of 1-substituted apomorphines as dopaminergic agonists were synthesized according to our new strategy employing the acid-catalyzed rearrangement of diversely functionalized 5β-substituted-6-demethoxythebaines. The activities of new compounds for dopamine receptors subtypes were evaluated using HEK293 based stable cell lines expressing D1, D2L or D3 receptor subtypes. All studied compounds had affinities in nanomolar range for D2L and D3 receptors and the change of the nature of substituent in position 1 had only moderate effect. D1 receptors were sensitive to the introduction of the 4-OH-benzyl function resulting in an increased affinity. The small hydrophilic group (hydroxymethyl) highly reduced the agonist affinity and potency thereby increasing subtype selectivity. This strategy for selective modulation of affinities and potencies of 1-substituted apomorphines gives essential hints for future design of subtype selective dopaminergic ligands., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A series of N-(2-methoxyphenyl)homopiperazine analogs was prepared and their affinities for dopamine D2, D3, and D4 receptors were measured using competitive radioligand binding assays. Several ligands exhibited high binding affinity and selectivity for the D3 dopamine receptor compared to the D2 receptor subtype. Compounds 11a, 11b, 11c, 11f, 11j and 11k had K(i) values ranging from 0.7 to 3.9 nM for the D3 receptor with 30- to 170-fold selectivity for the D3 versus D2 receptor. Calculated logP values (logP=2.6-3.6) are within the desired range for passive transport across the blood-brain barrier. When the binding and the intrinsic efficacy of these phenylhomopiperazines was compared to those of previously published phenylpiperazine analogues, it was found that (a) affinity at D2 and D3 dopamine receptors generally decreased, (b) the D3 receptor binding selectivity (D2:D3 K(i) value ratio) decreased and, (c) the intrinsic efficacy, measured using a forskolin-dependent adenylyl cyclase inhibition assay, generally increased., (Copyright © 2013. Published by Elsevier Ltd.)

The goal of the present study was to explore, in our previously developed hybrid template, the effect of introduction of additional heterocyclic rings (mimicking catechol hydroxyl groups as bioisosteric replacement) on selectivity and affinity for the D3 versus D2 receptor. In addition, we wanted to explore the effect of derivatization of functional groups of the agonist binding moiety in compounds developed by us earlier from the hybrid template. Binding affinity (K(i)) of the new compounds was measured with tritiated spiperone as the radioligand and HEK-293 cells expressing either D2 or D3 receptors. Functional activity of selected compounds was assessed in the GTPγS binding assay. In the imidazole series, compound 10a exhibited the highest D3 affinity whereas the indole derivative 13 exhibited similar high D3 affinity. Functionalization of the amino group in agonist (+)-9d with different sulfonamides derivatives improved the D3 affinity significantly with (+)-14f exhibiting the highest affinity. However, functionalization of the hydroxyl and amino groups of 15 and (+)-9d, known agonist and partial agonist, to sulfonate ester and amide in general modulated the affinity. In both cases loss of agonist potency resulted from such derivatization., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A series of mono-substituted 4-phenylpiperidines and -piperazines have been synthesized and their effects on the dopaminergic system tested in vivo. The structure activity relationship (SAR) revealed that the position and physicochemical character of the aromatic substituent proved to be critical for the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) in the brain of freely moving rats. In order to investigate how the structural properties of these compounds affect the response, a set of tabulated and calculated physicochemical descriptors were modeled against the in vivo effects using partial least square (PLS) regression. Furthermore, the binding affinities to the dopamine D2 (DA D2) receptor and monoamine oxidase A (MAO A) enzyme were determined for a chosen subset and QSAR models using the same descriptors as in the in vivo model were produced to investigate the mechanisms leading to the observed DOPAC response. These models, in combination with a strong correlation between the levels of striatal DOPAC and the affinities to DA D2 and MAO A, provides a comprehensive understanding of the biological response for compounds in this class., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

The actions of the predominant neurotransmitter in the brain, dopamine, are mediated by the postsynaptic dopamine receptors. The five dopamine receptor subtypes and their regulation have been associated with a large variety of psychiatric diseases. Therefore, positron emission tomography (PET) imaging studies using suitable and selective (18) F-labeled and (11) C-labeled dopamine receptor radioligands could provide valuable knowledge on the impact of receptor density on the pathogenesis and evolvement of neuropsychiatric and neurological diseases. This special issue subchapter provides a summary of the most important (18) F-labeled and (11) C-labeled radioligands for PET imaging of the dopamine receptor subtypes, their radiochemistry, and characteristics from in vitro and in vivo applications, considering not only the already established PET ligands but also the recently published preclinical work., (Copyright © 2013 John Wiley & Sons, Ltd.)

Aim: To design and synthesize bivalent ligands for adenosine A1-dopamine D1 receptor heteromers (A1-D1R), and evaluate their pharmacological activities., Methods: Bivalent ligands and their corresponding A1R monovalent ligands were designed and synthesized. The affinities of the bivalent ligands for A1R and D1R in rat brain membrane preparation were examined using radiolabeled binding assays. To demonstrate the formation of A1-D1R, fluorescence resonance energy transfer (FRET) was conducted in HEK293 cells transfected with D1-CFP and A1-YFP. Molecular modeling was used to analyze the possible mode of protein-protein and protein-ligand interactions., Results: Two bivalent ligands for A1R and D1R (20a, 20b), as well as the corresponding A1R monovalent ligands (21a, 21b) were synthesized. In radiolabeled binding assays, the bivalent ligands showed affinities for A1R 10-100 times higher than those of the corresponding monovalent ligands. In FRET experiments, the bivalent ligands significantly increased the heterodimerization of A1R and D1R compared with the corresponding monovalent ligands. A heterodimer model with the interface of helixes 3, 4, 5 of A1R and helixes 1, 6, 7 from D1R was established with molecular modeling. The distance between the two ligand binding sites in the heterodimer model was approximately 48.4 Å, which was shorter than the length of the bivalent ligands., Conclusion: This study demonstrates the existence of A1-D1R in situ and a simultaneous interaction of bivalent ligands with both the receptors.

Dopamine (D(2)) partial agonists (D2PAs) have been regarded as a potential treatment for schizophrenia patients with expected better side effect profiles than currently marketed antipsychotics. Herein we report the synthesis and SAR of a series of aminothiazole fused benzazepines as selective D(2) partial agonists. These compounds have good selectivity, CNS drug-like properties and tunable D(2) partial agonism. One of the key compounds, 8h, has good in vitro/in vivo ADME characteristics, and is active in a rat amphetamine-induced locomotor activity model., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The structural and functional interaction between D₂ dopamine receptor (DR) and A(2A) adenosine receptor (AR) has suggested these two receptors as a pharmacological target in pathologies associated with dopamine dysfunction, such as Parkinson's disease. In transfected cell lines it has been demonstrated the activation of D₂DR induces a significant negative regulation of A(2A)AR-mediated responses, whereas few data are at now available about the regulation of A(2A)AR by D₂DR agonists at receptor recognition site. In this work we confirmed that in A(2A)AR/D₂DR co-transfected cells, these receptors exist as homo- and hetero-dimers. The classical D₂DR agonists were able to negatively modulate both A(2A)AR affinity and functionality. These effects occurred even if any significant changes in A(2A)AR/D₂DR energy transfer interaction could be detected in BRET experiments. Since the development of new molecules able to target A(2A)/D₂ dimers may represent an attractive tool for innovative pharmacological therapy, we also identified a new small molecule, 3-(3,4-dimethylphenyl)-1-(2-piperidin-1-yl)ethyl)piperidine (compound 1), full agonist of D₂DR and modulator of A(2A)-D₂ receptor dimer. This compound was able to negatively modulate A(2A)AR binding properties and functional responsiveness in a manner comparable to classical D₂R agonists. In contrast to classical agonists, compound 1 led to conformational changes in the quaternary structure in D₂DR homomers and heteromers and induced A(2A)AR/D₂DR co-internalization. These results suggest that compound 1 exerts a high control of the function of heteromers and could represent a starting point for the development of new drugs targeting A(2A)AR/D₂ DR heteromers., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The neuromodulatory peptide neurotensin has been described to functionally interact with dopaminergic pathways of the human brain. We employed radioligand binding studies to investigate the physical interaction between co-expressed dopamine D(2L) or D₃ and neurotensin NTS₁ or NTS₂ receptors. Substantial cross-inhibitory effects of both receptor subtypes NTS(1) and NTS₂ on the agonist binding of D(2L) or D₃ were detected in the presence of neurotensin. To identify ligand-specific modulation and subtype-dependent differences, the novel dopamine receptor agonists 5 and 6 bearing the 7-OH-DPAT pharmacophore were synthesized. Exceptional ligand specificity was observed for D₃-NTS₂ co-expression, which gave a 20-fold decrease in affinity for biphenylcarboxamide 5 in the presence of neurotensin. Comparing the binding properties of dopaminergic compounds in the presence of neurotensin, dopamine receptor subtype-selective profiles of the cross-inhibitory effect of neurotensin were observed., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Efforts to develop selective agonists for dopamine D(1)-like receptors led to the discovery of dihydrexidine and doxanthrine, two bioisosteric β-phenyldopamine-type full agonist ligands that display selectivity and potency at D(1)-like receptors. We report herein an improved methodology for the synthesis of substituted chromanoisoquinolines (doxanthrine derivatives) and the evaluation of several new compounds for their ability to bind to D(1)- and D(2)-like receptors. Identical pendant phenyl ring substitutions on the dihydrexidine and doxanthrine templates surprisingly led to different effects on D(1)-like receptor binding, suggesting important differences between the interactions of these ligands with the D(1) receptor. We propose, based on the biological results and molecular modeling studies, that slight conformational differences between the tetralin and chroman-based compounds lead to a shift in the location of the pendant ring substituents within the receptor., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Carbon-11 labelled (+)-4-Propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol ([(11)C]-(+)-PHNO) is used as a high-affinity state, dopamine D(2/3) receptor ligand in clinical PET studies. To facilitate its use, robust, rapid, efficient and GMP compliant methods are required for the manufacturing and QC testing processes. Additionally, to allow for full quantification of the resulting signal in the CNS, a reliable method is required to establish the parent plasma concentration over the course of the scan. This paper provides high-quality methods to support clinical application of [(11)C]-(+)-PHNO., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Direct functionalization and tandem processes have both received considerable recent interest due to their cost and time efficiency. Herein we report the synthesis of difficult to obtain 2-substituted pyrazolo[1,5-a]pyridines through a tandem palladium-catalyzed/silver-mediated elimination/direct functionalization/cyclization reaction involving N-benzoyliminopyridinium ylides. As such, these biologically important molecules are prepared in an efficient, high-yielding manner, only requiring a two-step sequence from pyridine. Aryl-substituted alkenyl bromides and iodides are effective ylide coupling partners. Mechanistic studies led to the use of terminal alkynes, which extended the scope of the reaction to include alkyl substitution on the unsaturated reactive site. The optimization, scope, and mechanistic considerations of the process are discussed.

To probe the space at the floor of the orthosteric ligand binding site in the dopamine D(1) receptor, four methylated analogues of dihydrexidine (DHX) were synthesized with substitutions at the 7 and 8 positions. The 8α-axial, 8β-equatorial, and 7α-equatorial were synthesized by photochemical cyclization of appropriately substituted N-benzoyl enamines, and the 7β-axial analogue was prepared by an intramolecular Henry reaction. All of the methylated analogues displayed losses in affinity when compared to DHX (20 nM): 8β-Me(ax)-DHX (270 nM), 8α-Me(eq)-DHX (920 nM), 7β-Me(eq)-DHX (6540 nM), and 7α-Me(ax)-DHX (>10000 nM). Molecular modeling studies suggest that although the disruption of an aromatic interaction between Phe203(5.47) and Phe288(6.51) is the cause for the 14-fold loss in affinity associated with 8β-axial substitution, unfavorable steric interactions with Ser107(3.36) result in the more dramatic decreases in binding affinity suffered by the rest of the analogues.

A series of microPET imaging studies were conducted in anesthetized rhesus monkeys using the dopamine D₃-selective partial agonist, [¹⁸F]5. There was variable uptake in regions of brain known to express a high density of D₃ receptors under baseline conditions. Pretreatment with lorazepam (1 mg/kg, i.v. 30 min) to reduce endogenous dopamine activity before tracer injection resulted in a dramatic increase in uptake in the caudate, putamen, and thalamus, and an increase in the binding potential (BP) values, a measure of D₃ receptor binding in vivo. These data indicate that there is a high level of competition between [¹⁸F]5 and endogenous dopamine for D₃ receptors in vivo., (Copyright © 2011 Wiley-Liss, Inc.)

A set of novel apomorphine derivatives were synthesized with diversely functionalized side chains in the proximity of position 2 of the aporphine skeleton. Amino and/or carboxylic functions were introduced to this region of the backbone to test their pharmacological effects. During the synthesis of 2-(S-3-mercaptopropionic acid)-derivative a heteroring-fused congener was also isolated. The structural elucidation confirmed that the formation of this product was in accordance with our previous observations on the reaction of thebaine (2) with thiosalycilic acid. All the novel apomorphine congeners 4a-g were neuropharmacologically characterized to discover their dopaminergic profiles. Two derivatives were identified as D(2) full agonists equipotent with apomorphine (1) having significantly increased D(2)/D(1) selectivity ratios., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

A-86929, a dopamine D1 agonist was synthesized with 95% ee in five steps with overall yield of 56% via catalytic enantioselective one-pot aziridination followed by Friedel-Crafts cyclization and a mild Pictet-Spengler cyclization protocol.

A dihydroquinolinone moiety was found to be a potent serotonin reuptake inhibitor pharmacophore when combined with certain amines. This fragment was coupled with selected D(2) ligands to prepare a series of dual acting compounds with attractive in vitro profiles as dopamine D(2) partial agonists and serotonin reuptake inhibitors. Structure-activity studies revealed that the linker plays a key role in contributing to D(2) affinity, function, and SRI activity., (2010 Elsevier Ltd. All rights reserved.)

On the basis of previous work on dopaminergic partial agonists of type 1 and 2, disubstituted ferrocenes are presented as valuable arene bioisosteres. Because substituents at the distal cyclopentadienyl ring are able to adjust the relative disposition that is required for ligand binding, disubstituted ferrocenes can act as molecular hinges. Taking advantage of click chemistry, the regioselective construction and functionalization of the target molecules is reported. Thus triazole derived appendages were used for the fine-tuning of biological activity and for the attachment of linker units generating bivalent GPCR ligands. Receptor binding was evaluated by radioligand displacement experiments, revealing superaffinity with sub- to single-digit nanomolar K(i) values for particular test compounds. As a neutral antagonist at the dopamine receptors D3 and D4 and a potent partial agonist at the D2 subtype (intrinsic activity = 57%, EC(50) = 2.5 nM), the bifunctional ferrocene 10b revealed a novel and unique activity profile.

A 5-fluoro-tetrahydrocarbazole serotonin reuptake inhibitor (SRI) building block was combined with a variety of linkers and dopamine D2 receptor ligands in an attempt to identify potent D2 partial agonist/SRI molecules for treatment of schizophrenia. This approach has the potential to treat a broader range of symptoms compared to existing therapies. Selected compounds in this series demonstrate high affinity for both targets and D2 partial agonism in cell-based and in vivo assays.

A convenient route for the synthesis of some 2-propen-1-one derivatives with E isomeric configuration is described. The activity of the synthesized compounds was evaluated through behavioral studies of apomorphine-induced licking in animal models. It was demonstrated that most of the synthesized compounds showed moderate activity in inhibition of lickings, among which 6a, was the most active compound at 30 mg/kg.

We have presented the synthesis of novel thiazolo- and isothiazolo-apomorphines 12-17 resulting-in part-from an unexpected isomerization step occurred during the acid-catalyzed rearrangement of precursor thiazolo-morphinandienes 3-5. These 2,3-disubstituted apomorphines represent a new group of A-ring substituted aporphines. The receptor binding studies revealed that with the exception of two derivatives all the tested compounds have limited affinity for dopamine-receptor subtypes. Functional calcium assay for the most active isothiazolo-apomorphine showed higher affinities for D(1) and D(2L) subtypes. The docking of these ligands has been modelled to human D(2) and D(3 )receptors. On the basis of the predicted models, we identified an important cation-p interaction for the binding of isothiazolo-apomorphine 16.

A series of nitrogen-containing benzoheterocyclic derivatives were synthesized and tested for their antipsychotic activities. Their structures were confirmed by 1H NMR and HR-MS. Preliminary in vitro pharmacological trials showed that most of the target compounds have high affinity with D2 and 5-HT(2A) receptors. Among the tested compounds, 20 exhibited the highest affinity and D2 partial agonist activity. In vivo studies showed 20 has potent antipsychotic activities on apomorphine mice model, which is a chance to find a better precursor of D2 partial agonist for further optimization.

A series of racemic 6-aryl substituted 1-phenylbenzazepines 7a-e, and 17a,b were prepared. All these compounds showed binding potencies compatible to or much higher than that of the prototypic (+/-)-SKF-38393 ((+/-)-1) and (+/-)-SKF-83959 (3) for the D(1) receptor. Among analogs of (+/-)-SKF-38393, compounds 7b, 7c and 7e possess 10-, 2- and 7-fold enhancement in binding for the D(1) receptor, respectively. Lower but compatible potency to that of (+/-)-1 was observed for compounds 7a and 7d. The optimal 6-substituents (m-tolyl, and 2'-naphthyl) were applied to the skeleton of (+/-)-SKF-83959 (3). The resulting compounds 17a,b displayed high affinity at the D(1) receptor, only slightly lower than that of 3. These two compounds also showed good binding at the D(2) receptor.

A series of compounds structurally related to pramipexole were designed, synthesized, and evaluated as ligands for the dopamine 3 (D3) receptor. Compound 12 has a K(i) value of 0.41 nM to D3 and a selectivity of >30000- and 800-fold over the D1-like and D2 receptors, respectively. Our in vivo functional assays showed that this compound is a partial agonist at the D3 receptor with no detectable activity at the D2 receptor.